Biodegradable polymers with pendant functional groups attached through amide bonds

ABSTRACT

Amide compounds are defined and are polymerized to create polyesters and polyurethanes having amide units bearing a pendant functional group, where the nitrogen atom of the amide group is part of the polymer backbone. The pendant functional group of the functionalized amide polymer may be modified or added by post polymerization functionalization of the functionalized amide polymer. The pendant functional group of the functionalized amide polymer may include a protecting group that may be removed after polymerization. The pendant functional groups of the functionalized amide polymers may be used to modulate the physical, chemical and biological properties of the polymers.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. patent application Ser. No.14/381,295 filed on Aug. 27, 2014, which claims priority from PCTapplication number PCT/US2013/28637 filed Mar. 1, 2013, which claimspriority from U.S. provisional patent application Ser. No. 61/605,518filed on Mar. 1, 2012, all of which are incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

One or more embodiments, provides functionalized amide polymers, methodsof using functionalized amide polymers, methods of preparingfunctionalized amide polymers, end functionalized amide compounds with apendant functional group that may be used in one or more embodiments toproduce functionalized amide polymers, and methods of preparing endfunctionalized amide compounds with a pendant functional group.

BACKGROUND OF THE INVENTION

Polymers made from step growth condensation are used in numerousapplications. The properties of these polymers are dependent upon thetype of monomer and the backbone structure. For example, polyethyleneterephthalate is used for the manufacture of bottles with excellentbarrier properties and nylon is useful for the manufacture of strongfibers. Usually, polymers made from step growth polymerization do nothave any pendant functional group present along the backbone. However,in several applications, especially for biomedical applications, itwould be very useful to have pendant functional groups along thebackbone that modulate the physical and chemical properties of thepolymers and can be used to provide optimum signaling cues in abiological environment. For example, poly(lactic acid) is commonly usedfor several biomedical applications since it is biodegradable and hasgood mechanical properties. However, it lacks any functional group alongthe backbone and cannot be used to provide any cues to interact with thebiological environment. The current invention describes polymers made bystep growth polymerization. These functional groups modulate thephysical, chemical and biological properties of the polymers. They canalso be used to conjugate appropriate groups to provide the desiredfunctional outcome.

SUMMARY OF THE INVENTION

A functionalized amide polymer according to the following structure:

where every X^(C) is a urethane group or every X^(C) is an ester group;R¹ and R² may be the same or different and are each hydrocarbon groups;and where R¹ and R² may be selected to join to create a heterocyclicgroup that includes the nitrogen atom as a hetero atom within theheterocyclic group, m and n represent repeating units of the polymer inrandom or block configuration, M¹ and M² are pendant functional groupD

The functionalize amide polymer of claim 1, M² is different from M¹.

A functionalized amide polymer comprising: a polymer backbone selectedfrom polyesters and polyurethanes; and an amide group with a pendantfunctional group, where the nitrogen atom of the amide group is part ofthe polymer backbone, with the proviso that the pendant functional groupis not a fatty oil.

The functionalize amide polymer of claim 3, wherein the polymer has anumber molecular weight of at least 10,000.

The functionalized amide polymer of claim 3, where the polymer includesa unit defined by:

where each X^(C) is a urethane group or an ester group; R¹ and R² may bethe same or different and are each hydrocarbon groups; R³ is aheterocyclic group that includes the nitrogen atom as a hetero atomwithin the heterocyclic group; y and z may be the same or different andare from 0 to 4, and M is a pendant functional group.

The functionalized amide polymer of claim 3, where the polymer includesa unit defined by:

where each X^(C) is a urethane group or an ester group; R¹ and R² may bethe same or different and are each hydrocarbon groups; R³ is aheterocyclic group that includes the nitrogen atom as a hetero atomwithin the heterocyclic group; y and z may be the same or different andare from 0 to 4, and R⁴ is a hydrocarbon group.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a graphical plot of Tg (° C.) versus percent compositionof a pendant functional group for one or more embodiments where twodifferent pendent functional groups are present.

FIG. 2 provides a graphical plot of contact angle versus percentcomposition of a pendant functional group for one or more embodimentswhere two different pendent functional groups are present

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In the present invention, an end functionalized amide compound having apendant functional group is polymerized to create polyesters andpolyurethanes having amide units bearing the pendant functional group.The different end functionalization lends itself to the creation of thedifferent polymers as will be described herein. In some embodiments,copolymers are created, with amide units thereof providing differentpendant functional groups, the amide units being in random or blockconfigurations. Herein, the end functionalized amide compound having apendant functional group may be referred to as the “amide compound” forbrevity.

In one embodiment, the amide compound is defined by formulas (I) and(II):

where X^(a) and X^(b) may be the same or different and are each selectedfrom a hydroxyl group and a carboxylic acid group; R¹ and R² may be thesame or different and are each hydrocarbon groups; R³ is a heterocyclicgroup that includes the nitrogen atom as a hetero atom within theheterocyclic group, and y and z may be the same or different and arefrom 0 to 4, and M is a pendant functional group. In some embodiments,one of X^(a) and X^(b) is a hydroxyl group while the other of X^(a) andX^(b) is a carboxylic acid group. It will be appreciated that theformulas (I) and (II) can be conceptualized as being related, in thatthe R¹ and R² of formula (I) join to create a heterocyclic grouprepresented by R³, the heterocyclic group including the nitrogen atom asa hetero atom within the heterocyclic group.

In one or more embodiments, M may be virtually any organic group. In oneor more embodiments, M may be an organic pendant functional group. Inone or more embodiments, M may be an organic pendant functional group,but excluding fatty oils In some embodiments, M is a group capable ofreacting with other reagents to provide a desired functionality in apost-polymerization functionalization step that will be describedherein. In other embodiments, M includes a protecting group thatprotects the M group from reacting with other reagents during monomercreation or polymer creation or both or during post functionalizationsteps, particularly with multifunctional polymers as described herein.

Representative examples of organic pendant functional groups include butare not limited to:

wherein x is from 0 to 6, and HAL denotes a halogen. It is specificallynoted that, thought specific number are provided for repeating unit of—CH2- in some of the above structures, the present invention can bepractice with x repeating units of those structures. Herein, it will beunderstood that Boc stands for tert-butyloxycarbonyl, TBS stands forditertbutyl dimethylsilyl, tBu stands for t-Butyl, Bn stands for benzyl.

Representative examples of groups suitable for post polymerizationfunctionalization include groups with azide, carboxylic acid, hydroxyl,amine, nitrile, furan, aldehyde/ketone, maleimide, propargyl, or halogenfunctionality.

Particular non-limiting examples include:

Representative examples of protected groups include M groups protectedwith tert-butyloxycarbonyl, pyridyl disulfide, t-Butyl, benzyl, ketal,and ditertbutyl dimethylsilyl. Non-limiting examples include:

In one or more embodiments, M may be an amino acid side chain. An aminoacid side chain is a group that includes a terminal functional group ofan amino acid. In one or more embodiments, the terminal functional groupof the amino acid is attached to a carbon chain or connecting group. Insome embodiments, the carbon chain is a different length than the chainof the corresponding amino acid. Representative examples of residues ofan amino acid side chain include, but are not limited to:

In one or more embodiments, R¹ and R² are hydrocarbon chains of a lengthof from 1 to 10 carbon atoms (C1 to C10). In one or more embodiments, R¹and R² are hydrocarbon chains of from 1 to 6 carbon atoms (C1 to C6). Inone or more embodiments, R¹ and R² are hydrocarbon chains of from 1 to 3carbons atoms (C1 to C3).

Specific examples of hydrocarbon groups suitable for use as R¹ and R²include, but are not limited to, an ethylene group.

In one or more embodiments, R³ is an organic group that forms aheterocycle with the nitrogen atom. In one or more embodiments, theorganic group of R3 may include oxygen as a heteroatom. In one or moreembodiments, the organic group of R3 is a hydrocarbon group. In one ormore embodiments, R³ is a hydrocarbon chain from 2 to 5 carbon atoms. Inone or more embodiments, R³ is a hydrocarbon chain from 4 to 5 carbonatoms. In one or more embodiments, R³ is a hydrocarbon chain of about 4carbon atoms.

In one or more embodiments, where X^(a) and X^(b) of formula (I) arehydroxyl groups, the amide compound is a diol defined by formulas (III)or (IV):

where R¹, R² , R³, y, z and M are selected as defined above.

In other embodiments of formula (III), R¹ and R² are ethylene(—CH₂CH₂—).

In other embodiments of formula (IV), R³ forms a pyrrolidine group withthe nitrogen atom. In other embodiments, R³ forms a pyrrolidine groupwith the nitrogen atom, and y is 0. In other embodiments, R³ forms apyrrolidine group with the nitrogen atom, and y is 1.

In one or more embodiments, where X^(a) and X^(b) of formula (I) arecarboxylic acid groups, the amide compound is a dicarboxylic aciddefined by formulas (V) or (VI):

where R¹, R², R³, y, z are and M are selected as defined above.

In other embodiments of formula (V), R¹ and R² hydrocarbons having from1 to 6 carbons (i.e., C1 to C6).

In other embodiments of formula (VI), R³ forms a pyrolidine group withthe nitrogen atom. In other embodiments, R³ forms a pyrolidine groupwith the nitrogen atom, and y is 3. In other embodiments, R³ forms apyrrolidine group with the nitrogen atom, and y is 4.

In one or more embodiments, where X^(a) of formula (I) is a hydroxylgroup and X^(b) is a carboxylic acid group, the amide compound is ahydroxyacid defined by formula (VII):

where R¹, R², R³, y, z and M are selected as defined above.

To avoid instances where the carboxylic acid end group and hydroxylmight react through and intra-molecular reaction, R¹ and R² are keptrelatively large. Thus, in other embodiments of formula (VII), R¹ is ahydrocarbon group of greater than C2 and R² is a hydrocarbon group of C2or greater.

In other embodiments of formula (VIII), R³ forms a pyrrolidine groupwith the nitrogen atom. In other embodiments, R³ forms a pyrrolidinegroup with the nitrogen atom, and y and z are 0 to 2. In otherembodiments, R³ forms a pyrrolidine group with the nitrogen atom, and yis 2, and z is 1.

In one or more embodiments, the end functionalized amide compound with apendant functional group may be prepared by reactingbis(hydroxyhydrocarbyl)amine with a functionalized ester.

In one or more embodiments, the bis(hydroxyhydrocarbyl)amine may bedefined by the formula (IX) and formula (X):

where X^(a), X^(b), R¹, R², R³ y and z are selected as described above.

In one or more embodiments, the functionalized ester may be defined bythe formula (XI):

where R⁵ is a hydrocarbon group, and M is selected as defined above.

Methods of reacting the bis (hydroxyhydrocarbyl)amine orhydroxyhydrocarbyl carboxylic acid amine with funtionalized ester asabove are known in the art as for example in Gaozza, C. H., J. Med.Chem., Vol. 8, pg. 400-01, (1965).

In other embodiments, the amide compounds may be prepared by reacting aprotected bis(hydrocarbyloxy)amine or protected hydroxyhydrocarbylcarboxylic acid amine with a functionalized carboxylic acid.

In one or more embodiments, the protected bis(hydrocarbyloxy)amine orprotected hydroxyhydrocarbyl carboxylic acid amine may be defined byformula (XII) and formula (XIII):

where X^(d) and X^(e) may be the same or different and are each selectedfrom an oxygen atom and an ester group, with the proviso that when oneof X^(d) or X^(e) is an ester group the other is an oxygen atom; R¹, R²and R3 may be selected as described above; and each XP may be the sameor different and are each protecting groups.

Examples of suitable protecting groups include, but are not limited to,a benzyl group or a t-butyl dimethyl silyl group.

In one or more embodiments, the functionalized carboxylic acid may bedefined by the formula (XIV):

where M is selected as defined above.

The protected bis(hydrocarbyloxy)amine and functionalized carboxylicacid are reacted by carbodiimide-mediated (EDC, i.e.,ethyl(dimethylaminopropyl) carbodiimide) coupling reaction to form aprotected version of the amide compound. Suitably solvents for thecoupling reaction include dimethylformamide (DMF).

In one or more embodiments, the protecting group may be removed with I₂in an alcohol. In these or other embodiments, a t-butyl dimethyl silylprotecting group may be removed with I₂ in methanol. In one or moreembodiments, the protecting group may be removed with H₂ in an alcoholwith the presence of a palladium catalyst. In these or otherembodiments, a benzyl protecting group may be removed with H₂ inmethanol with the presence of a palladium catalyst. Removal yields theamide compound.

In the present invention, the amide compounds as disclosed above arepolymerized to create polyesters and polyurethanes having amide unitsbearing the pendant functional group (i.e., M), where the nitrogen atomof the amide group is part of the polymer backbone. In one or moreembodiments, the pendant functional group of the functionalized amidepolymer may be modified or added by post polymerizationfunctionalization of the functionalized amide polymer. In one or moreembodiments, the pendant functional group of the functionalized amidepolymer may include a protecting group that may be removed afterpolymerization.

As previously mentioned, the nitrogen atom of the amide group is part ofthe polymer backbone, such that polymers herein can be generallyconceptualized by the structure below:

where

generally represents a polymer backbone selected from polyesters andpolyurethanes; and M are as described herein.

In one or more embodiments, the functionalized amide polymer may includea unit defined by formula (XV) and formula (XVI):

where X^(C) is an ester or urethane group; R¹, R² , R³, y and z areselected as described above. In one or more embodiments, these units arerepeating units in a polymer.

In one or more embodiments, the functionalized amide polymer may bedefined by formula (XVII) and formula (XVIII):

where each X^(C) is a urethane group or an ester group; R¹, R², R³, y, zand M are selected as described above, and R⁴ is a hydrocarbon group. Inone or more embodiments, these units are repeating units in a polymer.

The functionalized amide polymer may include multiple functionalizedamide units. In one or more embodiments, the functionalized amidepolymer may include two or more different amide units. In these or otherembodiments, the two or more different amide units may be in random orblock configurations.

In one or more embodiments, the functionalized amide polymer may bedefined by formula (XIX):

where every X^(C) is a urethane group or every all X^(C) is an estergroup; R¹, R², R⁴, are selected as described above, and where R¹ and R²may be selected to join to create a heterocyclic group that includes thenitrogen atom as a hetero atom within the heterocyclic group; M¹ isselected as described above for M; M² is selected from any functionalgroup, and m and n represent repeating units of the polymer in random orblock configuration. In some embodiments, M² is selected as describedabove for M, with the proviso that it is different from M¹.

In particular embodiments, the functional amide polymer may be amultifunctional polyester defined as below:

wherein M¹ and M² are different and are chosen as above.

In other embodiments, the functional amide polymer may be amultifunctional polyurethane defined as below:

wherein M¹ and M² are different and are chosen as above.

In one or more embodiments, the functionalized amide polymer may bedefined by formula (XX):

where X^(C) is an ester group; R¹ and R² are selected as describedabove, and where R¹ and R² may be selected to join to create aheterocyclic group that includes the nitrogen atom as a hetero atomwithin the heterocyclic group as described above; M¹ is selected asdescribed above for M; M² is selected from any functional group, and mand n represent random or alternating repeating units of the polymer. Insome embodiments, M² is selected as described above for M, with theproviso that it is different from M¹.

In other embodiments, the functional amide polymer may be amultifunctional polyurethane defined as below:

wherein M¹ and M² are different and are chosen as above.

While depicted above as a polymer with two different amide units, thefunctionalized amide polymer may in other embodiments have more than twoamide units. In one or more embodiments, the functionalized amidepolymer may have 3, 4, 5, 6, 7, 8, 9, 10, or more different amide units.

Polymer with adhesion properties may include a polymer with alternatingorganic pendant group and catechol pendant group in a polyester orpolyurethane. Representative examples of organic pendant groups for usein adhesives include, but are not limited to, ethyl, propyl phenyl,hydroxy and amine groups.

The amide compounds of this invention may be diols, dicarboxylic acidsor hydroxyacids as already described above. When they are hydroxyacids,polyester polymers can be prepared by stepwise self polymerization ofthe hydroxyacid compounds. When the amide compounds are diols, polymersmay be prepared by stepwise polymerization of the amide compounds with acomonomer, and, when the comonomer is a diacid, a polyester results,and, when the comonomer is a diisocyanate, a polyurethane results. Whenthe amide compounds are dicarboxylic acids, polymers may be prepared bystepwise polymerization of the amide compounds with a diol comonomer,and a polyester results.

In one or more embodiments, a functionalized amide polyester is preparedby self polymerizing a hydroxyacid amide compound of this invention, asdefined by formulas (VII) and (VIII). The hydroxyacids are polymerizedby carbodiimide-mediated (DIC, diisoproplycarbodiimide) couplingreaction in dichloromethane (or other suitable solvent).

In one or more embodiments, a random polymer configuration may beprepared by polymerizing a mixture of two or more hydroxyacid amidecompounds with different M groups.

In one or more embodiments, a block polymer configuration may beprepared by first polymerizing an amide compound having a first pendantM group. Following polymerization, the compound is endcapped with areactive end group. A second amide compound is polymerized with adifferent M group. Then end capping this second amide compound with acomplimentary end group suitable for reacting with the first end groupof the first polymer thereby joining them in a block configuration.Examples of complementary pairs of end groups include propargyl andazide (first exemplary pair) and thiol and ene (second exemplary pair).

In one or more embodiments, a functionalized polymers are prepared fromthe reaction product of a diol amide compound of this invention with acomonomer selected from diacids and diisocyanates. The diol amidecompound is defined above in formulas (III) and (IV).

In one or more embodiments, the comonomer is a diacid or diisocyanatedefined by:

X^(f)—R⁵—X^(f)

where X^(f) is selected from carboxylic acid groups and isocyanategroups, and R⁵ is a hydrocarbon group.

The hydrocarbon group R⁵ may be a linear, cyclic, or branchedhydrocarbon group. In the case of dicarboxylic acid, the R⁵ is ahydrocarbon group of from C2 to C8, in other embodiments, from C2 to C6,and in yet other embodiments C2 to C4. In the case of diisocyanates, theR⁵ is a hydrocarbon group of from C6 to C10, in other embodiments, fromC6 to C8, and in yet other embodiments C6.

In one or more embodiments, where each X^(f) is a carboxylic acid group,the comonomer is a dicarboxylic compound. Representative examples ofdicarboxylic compounds suitable for use as a comonomer include, but arenot limited to, succinic acid, glutaric acid, adipic acid, pimelic acid,and suberic acid.

In one or more embodiments, where each X^(f) is an isocyanate group, thecomonomer is a diisocyanate compound. Representative examples ofdiisocyanate compounds suitable for use as a comonomer include, but arenot limited to, hexamehylene diisocyanate and 1,3-phenylenediisocyanate.

In one or more embodiments, a functionalized amide polyester may beprepared by reacting a dicarboxylic comonomer with a diol amide compoundas defined by Formula (III). The diol amide compound and thedicarboxylic comonomer are polymerized by carbodiimide-mediated (DIC,diisoproplycarbodiimide) coupling reaction in dichloromethane (or othersuitable solvent). In one or more embodiments, a random polymerconfiguration may be prepared by polymerizing a mixture of two or morediol amide compounds with different M groups.

In one or more embodiments, a functionalized amide polyurethane may beprepared by reacting a diisocyanate comonomer with an end functionalizedamide compound with a diol amide compound as defined by Formula (III).The diol amide compound is reacted with the diisocyanate in the presentof tin(II)octoate in dichloromethane or DMF. In one or more embodiments,a random polymer configuration may be prepared by polymerizing a mixtureof two or more diol amide compounds with different M groups.

In one or more embodiments, functionalized polymers are prepared fromthe reaction product of a dicarboxylic acid amide compound of thisinvention with a diol comonomer. The dicarboxylic acid amide compound isdefined above in formulas (V) and (VI). The diol comonomer is defined bythe formula:

HO—R⁶—OH

The hydrocarbon group R⁶ may be a linear, cyclic, or branchedhydrocarbon group. In some embodiments, the R⁶ is a hydrocarbon group offrom C1 to C10, in other embodiment from C1 to C6. In one or moreembodiments, a random polymer configuration may be prepared bypolymerizing a mixture of two or more dicarboxylic acid amide compoundswith different M groups.

The molecular weight of the functionalized amide polymers of thisinvention may be determined through size exclusion chromatography. Inone or more embodiments, the functionalized amide polymers are made tohave a number average molecular weight from 10,000 to 200,000 g/mol. Inone or more embodiments, the functionalized amide polymers are made tohave a number average molecular weight from 20,000 to 160,000 g/mol. Thepolydispersity ranges from 1.1 to 2.0.

As mentioned herein, M can be chosen as a group capable of reacting withother reagents to provide a desired functionality in apost-polymerization functionalization step. In such instances, polymersare created, as above, and the M group is thereafter reacted with afunctionalizing group P to provide a desired pendant functionality.

P may be chosen to be a suitably protected amino acid and can be boundto a suitably chosen M group. Representative examples of amino acidsinclude, but are not limited to histidine, alanine, isoleucine,arginine, leucine, asparagine, lysine, aspartic acid, methionine,cysteine, phenylalanine, glutamic acid, threonine, glutamine,tryptophan, glycine, valine, proline, serine, and tyrosine.

P may be chosen to be suitably protected peptide and can be bound to asuitably chosen M group. Representative examples of peptides include butare not limited to GRGDS, RGD, and YIGSR.

In one or more embodiments, P is an imaging label. In one or moreembodiments, the imaging label is a fluorescence imaging label.Fluorescence imaging labels may be a group that emits light uponexcitation. Excitation energies may ultraviolet light, visible light, ora combination thereof. Emission energies may be visible light, infraredlight, near infrared or a combination thereof. Representative examplesof fluorescence imaging labels include, but are not limited to

In one or more embodiments, the imaging label may be a radiographicimaging label. Radiographic imaging labels may be a group that providesan electron density suitable to provide contrast on a radiogram.Representative examples of radiographic imaging labels include, but arenot limited to fluorine-19. In one or more embodiments, the radiographicimaging label may be an organic group where one or more hydrogen atomsis substituted with fluorine-19.

In one or more embodiments, P may be a polyethylene glycol chain.

The pendant functional groups of the functionalized amide polymers maybe used to modulate the physical, chemical and biological properties ofthe polymers.

In one or more embodiments, the pendant functional groups may be used toalter the solubility of polymer. For example, when M is hydroxyl ahomopolymer according to this invention will be water soluble. In one ormore embodiments, when a hydrophilic polymer is desired, the polymer mayinclude hydrophilic M groups. The hydrophilic M groups may be used incombination with another M group that may be used to provide a differentfunction. In other embodiments, when a hydrophobic polymer is desired,the polymer may include hydrophobic M groups. The hydrophobic M groupsmay be used in combination with another M group that may be used toprovide a different function. For example, an amphiphilic polymer can becreated by having repeating units of a hydrophobic M group and arepeating unit of a hydrophilic M group.

In the example section herein specific data is given regarding theeffect of pendant groups on water contact angles and Tg.

In one or more embodiments, the polymer will be biodegradable. Inparticular embodiments, the biodegradable polymer is a polyester.

While particular embodiments of the invention have been disclosed indetail herein, it should be appreciated that the invention is notlimited thereto or thereby inasmuch as variations on the inventionherein will be readily appreciated by those of ordinary skill in theart. The scope of the invention shall be appreciated from the claimsthat follow.

EXAMPLES Experimental Procedures for Synthesis of Functionalized Diols

General procedure for the synthesis of diols from functionalizedcarboxylic acids.

Diol 3a: Mono benzyl adipate (3.07 g, 13 mmol) and EDC (2.68 g, 13 mmol)were taken in the RB flask. In this 15 mL dry DMF was added and stirredfor 10 mins. To this activated carboxylic acid, compound 2a (3.33 g, 10mmol) dissolved in 5 mL in DMF was added and reaction was stirredovernight. After completion of reaction, DMF was removed under reducedpressure and compound was extracted with 100 mL ethyl acetate (EtOAc).The organic layer was washed with 10% NaHCO₃ solution and brine anddried over anhy. Na₂SO₄. The crude product was purified columnchromatography with Hexane-EtOAc. Yield=3.4g (61%)

¹H NMR(300 MHz, CDCl₃): δ 1.66-1.71(m, 4H), 2.37-2.44(m, 4H), 3.47(dd,J₁=4.98 Hz, J₂=5.27 Hz, 2H), 3.54(dd J₁=4.68, J₂=4.98 Hz, 2H), 3.76(t,J₁=4.98, J₂=5.27 Hz, 2H), 3.84(t, J=4.68 Hz, 4.98 Hz, 2H), 5.11(s, 2H),7.31-7.36(m, 5H). ¹³CNMR (75 MHz, CDCl₃): δ 24.5, 33.1, 50.4, 52.1,60.7, 61.5, 66.2, 128.2, 128.5, 135.9, 173.4, 174.9. (ESI-MS) Cal:309.36, Obs.=311.2+Na⁺

Diol 3b: Similar procedure was followed as per synthesis of 3a.Yield=75%.

¹H NMR (300 MHz, CDCl₃): δ 1.44 (s, 9H), 2.65(m, 4H), 3.57(m, 4H),3.85(m, 4H). ¹³C NMR :(75 MHz, CDCl₃) δ 28.0, 28.1, 30.6, 50.6, 52.1,60.7, 61.1, 80.8, 172.8, 173.6. (ESI-MS) Cal: 261.31, Obs.=261.9,261.31+Na⁺

General procedure for the synthesis of diols from ester derivatives offunctionalized carboxylic acids.

Diethanol amine 1a (1 euivalent) and ester derivative of functionalizedcarboxylic acid (1 euivalent) was taken in the RB flask and heated at70° C. for 8 hrs. Then this reaction mixture was purified by columnchromatography with DCM-MeOH as gradient solvent system. The pure diolwas dried and used for polymerization reaction.

Diol 3c: Yield=76% (12.0 g), ¹H NMR: (300 MHz, CDCl₃) δ1.16 (dd, 3H,J₁=7.61 Hz, J₂=7.32 Hz), 2.39-2.50 (m, 2H), 3.50-3.59(m, 4H),3.78-3.90(m, 4H). ¹³C NMR:(75 MHz, CDCl₃) δ 9.3, 26.7, 52.1, 60.6,176.2. (ESI-MS) Cal.=161.20, Obs.=162.3

Diol 3d: Yield=63% , ¹H NMR: (300 MHz, CDCl₃) δ 2.65-2.74(dd, J₁=7.61Hz, J₂=8.20 Hz, 2H), 2.95-3.00(dd, J₁=7.99 Hz, J₂=8.20 Hz, 2H), 3.42(t,J=4.98 Hz, 2H), 3.54-3.57(dd, J₁=4.39 Hz, J₂=4.98 Hz, 2H), 3.70(t,J=4.98 Hz, 2H), 3.85(t, J=4.68 Hz, 2H), 7.21-7.32(m, 5H). ¹³C NMR :(75MHz, CDCl₃) δ 31.4, 35.3, 50.6, 52.1, 126.2, 128.4, 141.0, 174.5.(ESI-MS) Cal.=237.29, Obs.=238.2, 237.2 +Na⁺

Diol 3e: Yield: ¹H NMR: (300 MHz, CDCl₃) δ1.34-1.55(m, 13H),1.63-1.73(m, 2H), 2.41(t,=7.32 Hz, 2H), 3.10(t, J=6.73 Hz, 2H),3.49-3.57 (m, 4H), 3.77-3.86 (m, 4H). ¹³C NMR :(75 MHz, CDCl₃) δ 24.6,26.2, 28.4, 29.6, 33.2, 40.2, 50.4, 52.1, 60.6, 61.3, 79.1, 156.2, 175.2(ESI-MS) Cal.=318.41, Obs.=319.3.

Diol 3f: Yield=50% ¹H NMR: (300 MHz, CDCl₃) δ 0.08 (s, 6H), 0.9(s, 9H),2.68(t, 2H, J=6.15 Hz), 3.28 (bs, 2H), 3.57-3.6 (m, 4H), 3.78-3.87(m,4H), 3.99 (dd, 2H, J=615 Hz, 6.44 Hz) 13C NMR :(75 MHz, CDCl₃) δ-5.5,18.2, 25.8, 36.2, 50.8, 60.5, 61.5, 173.87. (ESI-MS) Cal.=291.46,Obs.=292.1, 291.46+Na⁺

Diol 3g: Yield=50% ¹H NMR: (300 MHz, CDCl₃) δ 1.42-1.49(m, 2H),1.60-1.72(m, 4H), 2.41-2.46(m, 2H), 3.27-3.31(m, 4H), 3.50-3.59(m, 4H),3.78-3.89(m, 4H), 13C NMR :(75 MHz, CDCl₃) δ 24.6, 26.3, 28.6, 33.2,50.4, 51.2, 61.2, 175.0. (ESI-MS) Cal.=244.29, Obs.=244.29+Na⁺

Diol 3h: Yield=78% ¹H NMR: (300 MHz, CDCl₃+DMSO) δ 2.61-2.21(m, 1H),2.56-2.60(m, 2H), 2.72-2.89(m, 2H), 3.53(m, 2H), 3.72-3.81(m, 4H),3.99-4.10(m, 2H), 6.51(bs, 1H). ¹³C NMR: (125 MHz, CDCl₃) δ 27.7, 30.3,48.4, 50.4, 58.8, 72.8, 81.2, 171.3, 171.5. (ESI-MS) Cal.=242.27,Obs.=241.1+Na⁺

Experimental Procedures for Synthesis of Polyesters

Functional diol (1 equivalaent) and succinic acid (1 equivalaent) wereweighted accurately in the Rb flask. DPTS (0.2 equivalent) was added tothis and it was diluted with 10 mL dry DCM. Then this mixture was warmedup to 40° C. for 1-2 mins. and mixture was cooled back to 0° C. To thiscooled mixture DIC (3 equivalents) was added dropwise and reactionmixture was warmed to RT and stirred for 24 hrs. Then polymer wasprecipitated from cold iso-propanol/methanol and dried.

For the synthesis of copolymers with 2 or more functionalized diols andsuccinic acid, the total equivalents of diols were equivalent tosuccinic acid.

4a: Yield=70%, ^(1H) NMR: (300 MHz, CDCl₃) δ 1.15(t, J=7.46 Hz, 3H),2.39(d, J=7.46 Hz, 2H), 2.62(s, 4H), 3.61-3.71(m, 4H), 4.23-4.25(m, 4H)

4b: Yield=61.7%, ¹H NMR: (300 MHz, CDCl₃) δ 2.52-2.58(m, 4H), 2.66 (t,J=7.75 Hz, 2H), 2.97(m, J=7.46 Hz, 2H), 3.49-3.60(m, 4H), 4.10-4.23(m,4H), 7.18-7.30(m, 5H)

4c Yield=37.5%, ¹H NMR: (300 MHz, CDCl₃) δ 1.33-1.68(m, 15H), 2.36(dd,2H, J=7.32 Hz, 7.61 Hz), 2.61-2.63(m, 4H), 3.05-3.14(m, 2H),3.58-3.64(m, 4H), 4.22(br, 4H), 4.77(br, 1H)

4d OTBDMS protected Yield =31.1%, 1H NMR: (300 MHz, CDCl₃) δ 0.06 (s,6H), 0.89 (s, 9H), 2.58-2.63(m, 6H), 3.60-3.71(m, 4H), 3.93-3.97(m, 2H),4.24(m, 4H).

OH yield=72% ,¹H NMR: (300 MHz, CDCl₃) δ 2.50-2.61(m, 6H), 3.50-3.55(m,6H), 4.10-4.28(m, 4H)

4e: Yield=45.1%, ¹H NMR: (300 MHz, CDCl₃) δ 1.63-1.67 (m, 4H), 2.36-2.38(m, 4H), 2.59 (m, 4H), 3.56-3.60(m, 4H), 4.19-4.21 (m, 4H), 5.10 (s,2H), 7.36 (m, 5H)

4f: Yield=69.8%, ¹H NMR: (300 MHz, CDCl₃) δ 1.38-1.48(m, 2H),1.59-1.70(m, 4H), 2.36-2.41(m, 2H), 2.62(m, 4H), 3.27-3.32(m, 2H),3.61-3.63(m, 4H), 4.23(m, 4H)

4g_(m:n=)0.66:0.33:Yield=59.1%, ¹H NMR: (300 MHz, CDCl₃) δ 1.12-1.17(m,2H), 2.35-2.40(m, 2H), 2.53-2.69(m, 6H), 2.95-3.00(m, 1H), 3.54-3.61(m,5H), 4.14-4.23(m, 5H), 7.17-7.37(m, 2H)

4g_(m:n=0.5:0.5:) Yield=59.1%, ¹H NMR: (300 MHz, CDCl₃) δ 1.12-1.17(m,3H), 2.35-2.40(m, 2H), 2.53-2.69(m, 10H), 2.95-3.00(m, 2H), 3.54-3.60(m,8H), 4.14-4.23(m, 8H), 7.16-7.30(m, 6H)

4g_(m:n=0.25:0.75) Yield=67.8%, ¹H NMR: (300 MHz, CDCl₃) δ 1.11-1.16(m,1H), 2.33-2.40(m, 1H), 2.51-2.68(m, 11H), 2.94-2.99(m, 3H), 3.52-3.68(m,8H), 4.11-4.22(m, 8H), 7.10-7.30(m, 8H)

4h_(m:n=0.9:0.1)—: Yield=69.4%, ¹H NMR: (300 MHz, CDCl₃) δ 1.44(s, 4H),2.52-2.68(m, 30H), 2.95-3.00(m, 9H), 3.51-3.61(m, 20H), 4.12-4.24(m,20H), 7.17-7.29(m, 23H)

4h_(m:n=)0.75:0.25: Yield=66.5%, ¹H NMR: (500 MHz, CDCl₃) 61.44(s, 9H),2.52-2.68(m, 26H), 2.96-2.99(m, 6H), 3.49-3.65(m, 16H), 4.14-4.22(m,16H), 7.17-7.29(m, 15H)

4h_(m:n=)0.6:0.4: yield=66.7%, ¹H NMR: (300 MHz, CDCl₃) δ 1.44(s, 9H),2.52-2.69(m, 17H), 2.95-3.00(m, 3H), 3.54-3.65(m, 10H), 4.14-4.24(m,10H), 7.20-7.28(m, 7H)

4i_(m:n=)0.9:0.1—: Yield=69.4%, ¹H NMR: (300 MHz, CDCl₃) δ 1.13(s, 1H),2.51-2.67(m, 6H), 2.93-2.99(m, 2H), 3.50-3.60(m, 5.0H), 4.10-4.23(m,5.0H), 7.17-7.29(m, 5H)

4j_(m:n=)0.75:0.25: Yield=66.5%, ¹H NMR: (500 MHz, CDCl₃) δ 1.44 (s,2H), 2.52-2.67 (m, 6H), 2.96-2.99 (m, 1.5H), 3.49-3.65(m, 4.2H),4.13-4.22 (m, 4H), 7.17-7.29(m, 5H)

4i_(m:n=)0.5:0.5: Yield=66.7%, ¹H NMR: (300 MHz, CDCl₃) δ 1.44(s, 6H),2.52-2.69(m, 12H), 2.95-3.00(m, 2H), 3.54-3.65(m, 7H), 4.41-4.24(m, 7H),7.20-7.28(m, 5H)

With reference to FIG. 1, it can be seen that the glass transitiontemperature is affected by the types and compositional percentages ofthe functional pendant group. FIG. 1 compares compositions 4g and 4i.

4j_(m:n=)0.5:0.5: yield=65%, ¹H NMR: (300 MHz, CDCl₃) δ 1.22-1.26(m,1H), 1.38-1.68(m, 15H), 2.37(m, 2H), 2.56-2.74(m, 12H), 3.10-3.12(m,2H), 3.62-3.67(m, 8H), 4.02(m, 2H), 4.24(m, 8H)

4k_(m:n=)0.5:0.5: yield=40%, ¹H NMR: (300 MHz, CDCl₃, TMS) δ1.33-1.50(m, 19H), 2.36-2.39(m, 6H), 2.61(br, 8H), 3.11(br, 2H),3.59(br, 8h), 4.22(br, 8h), 5.10(s, 2h), 7.35(m, 5H).

4l_(mn=0.75:0.25) : OTBS protected product: yield=72%, ¹H NMR: (300 MHz,CDCl₃) 60.06(s, 4H), 0.89(s, 7H), 2.58-2.70(m, 7H), 2.96-3.01(m, 1H),3.54-3.69(m, 4H), 3.93-3.97(m, 2H), 4.10-4.24(m, 4H), 7.22-7.34(m, 2H).OH_(m:n=0.75:0.25): yield=65%, ¹H NMR: (300 MHz, DMSO-d₆) 2.5-2.88(m,DMSO, 3H), 3.51-3.64(m, 13H), 4.10-4017(m, 5H), 4.59(br, 1H),7.17-7.23(m, 2H).

4l_(m:n=)0.5:0.5: yield=80%, ¹H NMR: (300 MHz, CDCl₃) 62.53-2.99(m,14H0, 3.53-3.62(m, 8H), 4.14-4.24(m, 8H), 4.68(m, 2H), 7.20-7.27(m, 5H)OH_(m:n−0.5:0.5):yield=80%, ¹H NMR: (300 MHz, CDCl₃) δ2.53-2.99(m, 14H0,3.53-3.62(m, 8H), 4.14-4.24(m, 8H), 4.68(m, 2H), 7.20-7.27(m, 5H).

4l_(mn=0.25:0.75) :yield=72%,¹H NMR: (300 MHz, CDCl₃) δ 0.05(s, 1H),0.88(s, 2H), 2.52-2.66(m,6H), 2.95-3.00(m, 2H), 3.53-3.68(m, 4H),3.92-3.96(m, 1H), 4.13-4.22(m, 4H), 7.14-7.30(m, 5H).OH_(m:n=0.25:0.75): yield=93%, ¹H NMR: (300 MHz, CDCl₃) δ 2.52-2.70(m,6H), 2.94-2.99(m, 2H), 3.53-3.68(m, 4H), 4.14-4.22(m, 4H), 4.68(br, 1H),7.20-7.37(m, 4H).

With reference to FIG. 2, it can be seen that the water contact angle isaffected by the types and compositional percentages of the functionalpendant group. FIG. 2 compares compositions 4g and 4l.

4m_(m:n=0.8:0.2) Yield=63.7%, ¹H NMR: (300 MHz, CDCl₃) δ 1.14(t, J=7.46Hz, 12H), 1.65(s, 8H), 2.38(t, J=7.46 Hz, 8H), 2.57-2.62(m, 22H),2.87(t, J=7.75 Hz, 2H), 3.57-3.62(m, 20H), 4.17-4.24(m, 20H), 6.62(s,3H)

The 4m polymer includes adhesion properties, and its fabrication isshown below.

4n_(m:n=0.9:0.1) Yield=78%, ¹H NMR: (300 MHz, CDCl₃) δ 1.90-1.97(m, 2H),2.29-2.33(m, 2H), 2.52-2.38(m, 60H), 2.82(s, 2H), 2.97(t, J=7.61 Hz,18H), 3.45-3.61(m, 40H), 4.11-4.24(m, 40H), 6.24(s, 2H), 6.50(s, 2H),7.16-7.34(m, 50H)

Polymer 4o: yield=78%. ¹H NMR: (300 MHz, CDCl₃) δ 1.21-1.23(m, 2.5H),1.44(s, 9H), 2.36-2.73(m, 18H), 3.61-3.75(m, 10H), 4.01-4.03(m, 10H)

Conjugation of dyes to 4j

Conjugation of azido anthracene to 4j: Polymer 4j (0.1 g) was taken in 2mL of THF. To this solution CuBr (cat.) and 9-Methylenazidoanthracene(12% of propargyl group on polymer) were added and reaction was stirredfor 4hrs. Then polymer was precipitated in diethyl ether. Then polymerwas redissolved in 1 mL THF and this solution was dropped into 20 mLEDTA (20 mmol) solution to remove the cooper salts.

Conjugation of FITC to polymer 4j: Above polymer (0.1 g) was taken in 2mL of DCM, TIPS 50 μL was added to it. This solution was cooled to 0° C.and 2 mL of TFA was added to it and stirred for 2 hrs. at RT. ThenTFA-DCM mixture was removed under reduced pressure and polymer wasprecipitated from diethyl ether. Polymer was dried and used for reactionwith FITC. Above polymer was taken in 1 mL DMSO and FITC dissolved inDMSO (1% of amine groups in polymer) was added and reaction was stirredfor 2 hrs. Then polymer was precipitated from diethyl ether.

Synthesis of polymer and its functionalization and their cell adhesionstudies.

Polymer 4o: yield=78%. ¹H NMR: (300 MHz, CDCl₃) δ 1.21-1.23(m, 2.5H),1.44(s, 9H), 2.36-2.73(m, 18H), 3.61-3.75(m, 10H), 4.01-4.03(m, 10H)

Polymer 4o-COOH: Polymer 4o (1 g) was taken in 5 mL DCM and TIPS (0.5mL) was added it. After cooling this reaction mixture to 0° C., TFA (5mL) was added and reaction stirred at room temp for 2 Hrs. Then TFA wasdistilled under reduced pressure and polymer was precipitated in diethylether and dried. Yield=90%. ¹H NMR: (300 MHz, DMSO-d₆) δ 1.05-1.16(m,2.5H), 2.32-2.56(m, 18H, DMSO), 3.50-3.60(m, 10H), 3.83(m, 1H),4.10-4.18(m, 10H), 8.23(m, 0.5H)

Functionlization of polymer 4o-COOH with short PEG analogs and RGDpeptide

Coupling of 2-[2-(2-Methoxyethoxy)ethoxy)ethyl amine(PEGNH2) to carboxylgrou000p of Polymer Polymer 4o-COOH (0.1 g) was taken in 1 mL mixture ofCHCl₃-DMF (10:1) and DIC (12 μL, 55% of COOH group) was added to it.After 15 mins PEGNH2 (11.34 mg, 50% vof COOH groups) was added to it.Reaction was stirred for 2 hrs and then DIC (6 μL, 22% of COOH group)was added again for further activation. To this activated reactionmixture 2-phenyl ethylamine (4.3 μL, 20% of COOH groups) was added andreaction further stirred for 2 hrs. This functionalized polymer wasprecipitated from cold 2-propanol and centrifuged and dried.

4o-COOH+2-phenyl ethylamine (P): Similar procedure was followed as abovefor the functionalization of polymer 4o-COOH with 2-phenyl ethyl amine.

Spincoating of polymers on glass cover slips: Cover slips were cleanedby soaking them into ethanol-NaOH solution for 30 mins. Then washed withdistilled water and dried under strong stream of air making sure thecover slips were spot and debris free.

The polymers were spin coated from 2% (w/v) polymer solution in CHCl₃:DMF (10:1) mixture. Spin coating of polymers were carried out at 2500rpm for 1 min. Theses slides were then dried and used for furtherfunctionalization and contact angle measurements.

Surface Fuctionlization: The surface propargyl groups were reacted withazide terminated RGD peptide by Huisgen 1,3-cycloaddition reaction. Thereagent was prepared by mixing 0.5 mL of CuSO₄ (5 mM), 0.5 mL of sodiumascorbate (10 mM), and 0.25 mL of N₃-HA-GRGDS (2 mM). The propargylfunctionalized coverslips were inverted over a solution (50 μL) of theClick reagent and allowed to react for 4 h. Then these coverslips werewashed with deionized water and were inverted over 50 μL solution of 20mM EDTA solution and left for 4 hrs. These coverslips were washed againwith deionized water and dried under vacuum.

Polyurethanes Polymers

Synthesis of Polyurethanes from Functionalized Diols and HexamethyleneDiisocyanate

Experimental procedure: 5a and 5b: One equivalent of diol and oneequivalent of diisocyanate were added to a clean round bottom flaskunder inert atmosphere. The diol and diisocyanate were then dissolved indry CH₂Cl₂. The solution was stirred via magnetic stir bar for 10minutes before addition of a catalytic amount of tin octoate. Thereaction continued stirring at room temperature for 24-36 hours. Theresulting polymers were dissolved in chloroform and precipitated in colddiethyl ether.

5c: A feed ratio of 1:1:2 of Diol 1:Diol 2:Diisocyanate were added to aclean round bottom flask under inert atmosphere. The diols anddiisocyanates were then dissolved in dry DMF or dry CH₂Cl₂. The solutionwas stirred via magnetic stir bar for 10 minutes before addition of acatalytic amount of tin octoate. The reaction continued stirring at roomtemperature for 24-36 hours. The resulting polymers were dissolved inchloroform and precipitated in cold diethyl ether.

5a: Yield=78%, ¹H NMR: (300 MHz, CDCl₃) 1.24-1.36(m, 4H), 1.60-1.66(m,1H), 2.58-2.65(m, 1H0, 2.66(br, 1H), 2.84-3.02(m, 3H), 3.09(dd, J=11.6Hz, 6.44 Hz, 2H), 3.44-3.59(m, 2H), 4.06-4.22(m, 2h), 7.14-7.31(m, 6H).

5b: Yield=78%, ¹H NMR: (300 MHz, CDCl₃) 1.05-1.15(m, 3H), 1.26-1.36(m,5H), 1.41-1.51(m, 5H), 1.63-1.71(m, 1H), 2.31-2.40(m, 2H), 3.05-3.15(m,4H), 3.52-3.61(m, 4H), 4.13-4.23 (m, 4H).

5c: Yield=78% , ¹H NMR: (300 MHz, DMSo-d₆) 0.82-.91(m, 3H), 1.19-1.26(m,3H), 1.30-1.38(m, 4H), 1.48-1.60(m, 2H), 2.91-2.99(m, 3H), 3.40-3.56(m,9H), 3.97(br, 1H), 4.01-4.09(m, 2H), 8.30-8.33(m, 1H).

What is claimed is:
 1. A functionalized amide polymer comprising: apolyester backbone; an amide group with a pendant functional group,where the nitrogen atom of the amide group is part of the polymerbackbone.
 2. The functionalized amide polymer of claim 1, where thefunctionalized amide polymer includes a unit defined by formula (XV) orformula (XVI):

where each X^(C) is an ester group; R¹ and R² may be the same ordifferent and are each hydrocarbon groups; R³ is a heterocyclic groupthat includes the nitrogen atom as a hetero atom within the heterocyclicgroup; y and z may be the same or different and are from 0 to 4, and Mis a pendant functional group.
 3. The functionalized amide polymer ofclaim 1, where the functionalized amide polymer includes a unit definedby formula (XVII) or formula (XVIII):

where each X^(C) is an ester group; R¹ and R² may be the same ordifferent and are each hydrocarbon groups; R³ is a heterocyclic groupthat includes the nitrogen atom as a hetero atom within the heterocyclicgroup; y and z may be the same or different and are from 0 to 4, R⁴ is ahydrocarbon group, and M is a pendant functional group.
 4. Thefunctionalized amide polymer of claim 1, wherein the polymer has anumber average molecular weight (M_(n)) of at least 10,000 g/mol.
 5. Thefunctionalized amide polymer of claim 1, where the pendant functionalgroup is selected from the group consisting of organic pendantfunctional groups, amino acid side chains, and protected groups.
 6. Thefunctionalized amide polymer of claim 1, where the pendant functionalgroup is a group suitable for post polymerization functionalization andincludes a group selected from azides, carboxylic acids, hydroxyls,amines, nitriles, furans, aldehydes, ketones, maleimides, propargyls, orhalogens.
 7. The functionalized amide polymer of claim 1, where thependant functional group is selected from the group consisting ofimaging labels, peptides, and amino acids.
 8. The functionalized amidepolymer of claim 1, where the pendant functional group is an amino acidside chain selected from histidine, alanine, isoleucine, arginine,leucine, asparagine, lysine, aspartic acid, methionine, cysteine,phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine,valine, proline, serine, and tyrosine.
 9. The functionalized amidepolymer of claim 1, where the pendant functional group is selected from

wherein x is from 0 to 6, and HAL denotes a halogen.
 10. Thefunctionalized amide polymer of claim 1, where the pendant functionalgroup is selected from

wherein x is from 0 to 6, and HAL denotes a halogen.
 11. Thefunctionalized amide polymer of claim 1, where the pendant functionalgroup is selected from

wherein x is from 0 to 6, and HAL denotes a halogen.